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Advances in Topical and Transdermal Drug Delivery, 2nd Edition

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 18232

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Dr. Salette Reis

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Associate Professor, LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: medicinal chemistry; infectious, inflammatory and cancer diseases; nanotechnology and nanodelivery; development of “smart” drug systems; biophysics and drug-membrane interactions
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Dr. Sofia Lima

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LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: cell culture; colloids; magnetic nanoparticles; marine polysaccharides; liposomes; lipid nanoparticles; photothermal therapy; polymeric nanoparticles
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Dr. Tânia Moniz

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LAQV-REQUIMTE, Applied Chemistry Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: biochemistry; medicinal and pharmaceutical chemistry; drug delivery; nanotechnology; polymers; spectroscopy; fluorescence; metal ions; metallodrugs; skin; plants nutrition
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Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute a full article, short communication, or review article to a Special Issue entitled “Advances in Topical and Transdermal Drug Delivery—Volume II ”. The issue aims to cover the most recent advances and novel approaches in improving skin drug delivery.

Skin is the biggest organ in the human body, which represents an important drug administration route and is a place for the application of cosmetics and therapeutic agents. Transdermal drug delivery has attracted a great deal of attention as an alternative to the oral administration of drugs and hypodermic injections, mainly due to its many advantages such as improved bioavailability, more uniform plasma levels, longer duration (and thus reduced dosing frequency), enhanced patient compliance, and reduced systemic side effects.

However, this organ represents a great challenge for drug delivery since it blocks the entry of most cutaneously administered drugs. Therefore, different approaches have been developed to surmount these limitations. In this Special Issue, we will collect interesting solutions for overcoming the current drawbacks of skin drug delivery.

The knowledge obtained and the novel approaches will certainly contribute to improving the permeation of many active agents and will, therefore, allow the treatment of several disorders and the implementation of anti-ageing solutions.

We look forward to receiving your contributions.

Dr. Salette Reis
Dr. Sofia Lima
Dr. Tânia Moniz
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

therapeutic agent
skin absorption
cosmetic application
skin mimetic models
nanoparticles
hydrogels
microneedles

Published Papers (11 papers)

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Research

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18 pages, 3677 KiB

Open AccessEditor’s ChoiceArticle

New Formulation–Microporation Combination Approaches to Delivering Ciclopirox across Human Nails

by Juliana Kishishita, Camila de Almeida Perez Pimenta, Danielle Patricia Cerqueira Macedo, M. Begoña Delgado-Charro and Leila Bastos Leal

Pharmaceutics 2024, 16(1), 72; https://doi.org/10.3390/pharmaceutics16010072 - 04 Jan 2024

Viewed by 812

Abstract

Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina^® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina^® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina^®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients’ adherence. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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11 pages, 1943 KiB

Open AccessArticle

Topical Delivery Systems Effectively Transport Analgesics to Areas of Localized Pain via Direct Diffusion

by Thomas Birngruber, Kip Vought, Simon Schwingenschuh, Peter Reisenegger, Howard Maibach and Dmitri Lissin

Pharmaceutics 2023, 15(11), 2563; https://doi.org/10.3390/pharmaceutics15112563 - 31 Oct 2023

Viewed by 1012

Abstract

Topical delivery systems (TDSs) enable the direct transport of analgesics into areas of localized pain and thus minimize the side effects of administration routes that rely on systemic drug distribution. For musculoskeletal pain, clinicians frequently prescribe topical products containing lidocaine or diclofenac. This study assessed whether drug delivery from a TDS into muscle tissue occurs mainly via direct diffusion or systemic transport. An investigational TDS containing 108 mg lidocaine (SP-103, 5.4% lidocaine), a commercially available TDS containing 36 mg lidocaine (ZTlido^®, 1.8% lidocaine), and a topical pain relief gel (Pennsaid^®, 2% diclofenac) were tested. Using open flow microperfusion (OFM), interstitial fluid from the dermis, subcutaneous adipose tissue (SAT), and muscle was continuously sampled to assess drug penetration in all tissue layers. Ex vivo and in vivo experiments showed a higher diffusive transport of lidocaine compared to diclofenac. The data showed a clear contribution of diffusive transport to lidocaine concentration, with SP-103 5.4% resulting in a significantly higher lidocaine concentration in muscle tissue than commercially available ZTlido^® (p = 0.008). These results indicate that SP-103 5.4% is highly effective in delivering lidocaine into muscle tissue in areas of localized pain for the treatment of musculoskeletal pain disorders (e.g., lower back pain). Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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21 pages, 3251 KiB

Open AccessArticle

Investigation and Evaluation of the Transdermal Delivery of Ibuprofen in Various Characterized Nano-Drug Delivery Systems

by Jeanri Myburgh, Wilna Liebenberg, Clarissa Willers, Admire Dube and Minja Gerber

Pharmaceutics 2023, 15(10), 2413; https://doi.org/10.3390/pharmaceutics15102413 - 03 Oct 2023

Viewed by 1145

Abstract

The aim was to assess the suitability of three nano-based transdermal drug delivery systems containing ibuprofen: a nano-emulsion, a nano-emulgel, and a colloidal suspension with ibuprofen-loaded nanoparticles. Understanding the transdermal delivery of ibuprofen using nano-based drug delivery systems can lead to more effective pain relief and improved patient compliance. Characterization tests assessed the suitability of the developed drug delivery systems. Membrane release and skin diffusion studies, along with tape stripping, were performed to determine drug release and skin permeation of ibuprofen. In vitro cytotoxicity studies on HaCaT cells were conducted using MTT and neutral red assays to evaluate the safety of the developed drug delivery systems. Characterization studies confirmed stable drug delivery systems with ideal properties for transdermal delivery. Membrane release studies demonstrated the successful release of ibuprofen. In vitro skin diffusion experiments and tape stripping, detecting ibuprofen in the receptor phase, stratum corneum-epidermis, and epidermis-dermis, indicating successful transdermal and topical delivery. The in vitro cytotoxicity studies observed only minor cytotoxic effects on HaCaT cells, indicating the safety of the developed drug delivery systems. The investigation demonstrated promising results for the transdermal delivery of ibuprofen using the developed drug delivery systems, which contributes to valuable insights that may lead to improved pain management strategies. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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19 pages, 3974 KiB

Open AccessArticle

Beneficial Effects of Two Hydrogen Sulfide (H₂S)-Releasing Derivatives of Dexamethasone with Antioxidant Activity on Atopic Dermatitis in Mice

by Silvia Abigail Coavoy-Sánchez, Anderson Romério Azevedo Cerqueira, Simone Aparecida Teixeira, Vincenzo Santagada, Giorgia Andreozzi, Angela Corvino, Antonia Scognamiglio, Rosa Sparaco, Giuseppe Caliendo, Beatrice Severino, Soraia Katia Pereira Costa, Luis Carlos Spolidorio and Marcelo Nicolás Muscará

Pharmaceutics 2023, 15(7), 1907; https://doi.org/10.3390/pharmaceutics15071907 - 08 Jul 2023

Cited by 2 | Viewed by 1539

Abstract

Hydrogen sulfide (H₂S) is particularly produced in the skin, where it participates in the regulation of inflammation, pruritus, cytoprotection, scarring, and angiogenesis. In this study, we compared the effects of dexamethasone (Dex) with two H₂S-releasing Dex derivatives in a murine model of atopic dermatitis (AD) induced by topical application of 2,4-dinitrochlorobenzene (DNCB). After sensitization with DNCB, the animals were topically treated for five consecutive days with either the H₂S-releasing compounds 4-hydroxy-thiobenzamide (TBZ) and 5-(p-hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), Dex, or the derivatives Dex-TBZ or Dex-ADT. Topical treatment with equimolar doses of either Dex, Dex-TBZ, or Dex-ADT resulted in similar reductions in dermatitis score, scratching behavior, edema, eosinophilia, splenomegaly, and histological changes. In contrast with Dex, the H₂S-releasing derivatives prevented IL-4 elevation and oxidative modification of skin proteins. On an equimolar dose basis, Dex-TBZ, but not Dex-ADT, promoted the elevation of endogenous H₂S production and GPx activity. Neither Dex-TBZ nor Dex-ADT decreased GR activity or caused hyperglycemia, as observed with Dex treatment. We conclude that the presence of H₂S-releasing moieties in the Dex structure does not interfere with the anti-inflammatory effects of this corticosteroid and adds beneficial therapeutical actions to the parent compound. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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17 pages, 3655 KiB

Open AccessArticle

Immunometabolism Modulation by Extracts from Pistachio Stalks Formulated in Phospholipid Vesicles

by Simone Pani, Ilaria Pappalardo, Anna Santarsiero, Antonio Vassallo, Rosa Paola Radice, Giuseppe Martelli, Francesco Siano, Simona Todisco, Paolo Convertini, Carla Caddeo and Vittoria Infantino

Pharmaceutics 2023, 15(5), 1540; https://doi.org/10.3390/pharmaceutics15051540 - 19 May 2023

Cited by 1 | Viewed by 1335

Abstract

Several studies have demonstrated the effectiveness of plant extracts against various diseases, especially skin disorders; namely, they exhibit overall protective effects. The Pistachio (Pistacia vera L.) is known for having bioactive compounds that can effectively contribute to a person’s healthy status. However, these benefits may be limited by the toxicity and low bioavailability often inherent in bioactive compounds. To overcome these problems, delivery systems, such as phospholipid vesicles, can be employed. In this study, an essential oil and a hydrolate were produced from P. vera stalks, which are usually discarded as waste. The extracts were characterized by liquid and gas chromatography coupled with mass spectrometry and formulated in phospholipid vesicles intended for skin application. Liposomes and transfersomes showed small size (<100 nm), negative charge (approximately −15 mV), and a longer storage stability for the latter. The entrapment efficiency was determined via the quantification of the major compounds identified in the extracts and was >80%. The immune-modulating activity of the extracts was assayed in macrophage cell cultures. Most interestingly, the formulation in transfersomes abolished the cytotoxicity of the essential oil while increasing its ability to inhibit inflammatory mediators via the immunometabolic citrate pathway. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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14 pages, 1136 KiB

Open AccessArticle

Mixed Edge Activators in Ibuprofen-Loaded Transfersomes: An Innovative Optimization Strategy Using Box–Behnken Factorial Design

by João Vieira, Jéssica Castelo, Marta Martins, Nuno Saraiva, Catarina Rosado and Catarina Pereira-Leite

Pharmaceutics 2023, 15(4), 1209; https://doi.org/10.3390/pharmaceutics15041209 - 11 Apr 2023

Cited by 3 | Viewed by 1971

Abstract

Transfersomes have been highlighted as an interesting nanotechnology-based approach to facilitate the skin delivery of bioactive compounds. Nevertheless, the properties of these nanosystems still need to be improved to enable knowledge transfer to the pharmaceutical industry and the development of more efficacious topical medicines. Quality-by-design strategies, such as Box–Behnken factorial design (BBD), are in line with the current need to use sustainable processes to develop new formulations. Thus, this work aimed at optimizing the physicochemical properties of transfersomes for cutaneous applications, by applying a BBD strategy to incorporate mixed edge activators with opposing hydrophilic–lipophilic balance (HLB). Tween^® 80 and Span^® 80 were used as edge activators and ibuprofen sodium salt (IBU) was selected as the model drug. After the initial screening of the IBU solubility in aqueous media, a BBD protocol was implemented, and the optimized formulation displayed appropriate physicochemical properties for skin delivery. By comparing the optimized transfersomes to equivalent liposomes, the incorporation of mixed edge activators was found to be beneficial to upgrade the storage stability of the nanosystems. Furthermore, their cytocompatibility was shown by cell viability studies using 3D HaCaT cultures. Altogether, the data herein bode well for future advances in the use of mixed edge activators in transfersomes for the management of skin conditions. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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22 pages, 5423 KiB

Open AccessArticle

Development of Olive Oil Containing Phytosomal Nanocomplex for Improving Skin Delivery of Quercetin: Formulation Design Optimization, In Vitro and Ex Vivo Appraisals

by Omnia M. Hendawy, Mohammad M. Al-Sanea, Rehab Mohammed Elbargisy, Hidayat Ur Rahman, Hesham A. M. Gomaa, Ahmed A. B. Mohamed, Mohamed F. Ibrahim, Abdulsalam M. Kassem and Mohammed Elmowafy

Pharmaceutics 2023, 15(4), 1124; https://doi.org/10.3390/pharmaceutics15041124 - 31 Mar 2023

Cited by 2 | Viewed by 1294

Abstract

The objective of the current work was to fabricate, optimize and assess olive oil/phytosomal nanocarriers to improve quercetin skin delivery. Olive oil/phytosomal nanocarriers, prepared by a solvent evaporation/anti-solvent precipitation technique, were optimized using a Box–Behnken design, and the optimized formulation was appraised for in vitro physicochemical characteristics and stability. The optimized formulation was assessed for skin permeation and histological alterations. The optimized formulation (with an olive oil/PC ratio of 0.166, a QC/PC ratio of 1.95 and a surfactant concentration of 1.6%), and with a particle diameter of 206.7 nm, a zeta potential of −26.3 and an encapsulation efficiency of 85.3%, was selected using a Box–Behnken design. The optimized formulation showed better stability at ambient temperature when compared to refrigerating temperature (4 °C). The optimized formulation showed significantly higher skin permeation of quercetin when compared to an olive-oil/surfactant-free formulation and the control (~1.3-fold and 1.9-fold, respectively). It also showed alteration to skin barriers without remarkable toxicity aspects. Conclusively, this study demonstrated the use of olive oil/phytosomal nanocarriers as potential carriers for quercetin—a natural bioactive agent—to improve its skin delivery. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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12 pages, 2467 KiB

Open AccessArticle

Design and Evaluation of Dissolvable Microneedles for Treating Atopic Dermatitis

by Noa Ben David, Yuval Richtman, Adi Gross, Ruba Ibrahim, Abraham Nyska, Yuval Ramot and Boaz Mizrahi

Pharmaceutics 2023, 15(4), 1109; https://doi.org/10.3390/pharmaceutics15041109 - 31 Mar 2023

Cited by 3 | Viewed by 2698

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused predominantly by immune dysregulation. The global impact of AD continues to increase, making it not only a significant public health issue but also a risk factor for progression into other allergic phenotype disorders. Treatment of moderate-to-severe symptomatic AD involves general skin care, restoration of the skin barrier function, and local anti-inflammatory drug combinations, and may also require systemic therapy, which is often associated with severe adverse effects and is occasionally unsuitable for long-term use. The main objective of this study was to develop a new delivery system for AD treatment based on dissolvable microneedles containing dexamethasone incorporated in a dissolvable polyvinyl alcohol/polyvinylpyrrolidone matrix. SEM imaging of the microneedles showed well-structured arrays comprising pyramidal needles, fast drug release in vitro in Franz diffusion cells, an appropriate mechanical strength recorded with a texture analyzer, and low cytotoxicity. Significant clinical improvements, including in the dermatitis score, spleen weights, and clinical scores, were observed in an AD in vivo model using BALB/c nude mice. Taken together, our results support the hypothesis that microneedle devices loaded with dexamethasone have great potential as a treatment for AD and possibly for other skin conditions as well. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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13 pages, 2627 KiB

Open AccessCommunication

Design and Preclinical Evaluation of Nicotine–Stearic Acid Conjugate-Loaded Solid Lipid Nanoparticles for Transdermal Delivery: A Technical Note

by Jwala Renukuntla, Samuel Peterson-Sockwell, Bradley A. Clark, Nipunika H. Godage, Emanuela Gionfriddo, Pradeep Kumar Bolla and Sai H. S. Boddu

Pharmaceutics 2023, 15(4), 1043; https://doi.org/10.3390/pharmaceutics15041043 - 23 Mar 2023

Cited by 3 | Viewed by 1534

Abstract

This study aimed to develop and evaluate nicotine--stearic acid conjugate-loaded solid lipid nanoparticles (NSA-SLNs) for transdermal delivery in nicotine replacement therapy (NRT). Nicotine conjugation to stearic acid prior to SLN formulation greatly increased drug loading. SLNs loaded with a nicotine–stearic acid conjugate were characterized for size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency, and morphology. Pilot in vivo testing was carried out in New Zealand Albino rabbits. The size, PDI, and ZP of nicotine–stearic acid conjugate-loaded SLNs were 113.5 ± 0.91 nm, 0.211 ± 0.01, and −48.1 ± 5.75 mV, respectively. The entrapment efficiency of nicotine–stearic acid conjugate in SLNs was 46.45 ± 1.53%. TEM images revealed that optimized nicotine–stearic acid conjugate-loaded SLNs were uniform and roughly spherical in shape. Nicotine–stearic acid conjugate-loaded SLNs showed enhanced and sustained drug levels for up to 96 h in rabbits when compared with the control nicotine formulation in 2% HPMC gel. To conclude, the reported NSA-SLNs could be further explored as an alternative for treating smoking cessation. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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18 pages, 2481 KiB

Open AccessArticle

Derivatives of L-Ascorbic Acid in Emulgel: Development and Comprehensive Evaluation of the Topical Delivery System

by Aleksandra Stolić Jovanović, Milica Martinović, Ana Žugić, Ivana Nešić, Tomislav Tosti, Stevan Blagojević and Vanja M. Tadić

Pharmaceutics 2023, 15(3), 813; https://doi.org/10.3390/pharmaceutics15030813 - 02 Mar 2023

Cited by 4 | Viewed by 1649

Abstract

The dual controlled release of emulgels makes them efficient drug delivery systems of increasing interest. The framework of this study was to incorporate selected L-ascorbic acid derivatives into emulgels. From the formulated emulgels, the release profiles of actives were evaluated considering their different polarities and concentrations, and consequently their effectiveness on the skin via a long-term in vivo study that lasted for 30 days was determined. Skin effects were assessed by measuring the electrical capacitance of the stratum corneum (EC), trans-epidermal water loss (TEWL), melanin index (MI) and skin pH. In addition, the sensory and textural properties of emulgel formulations were compared with each other. The changes in the rate of the release of the L-ascorbic acid derivatives were monitored using the Franz diffusion cells. The obtained data were statistically significant, and indicated an increase in the degree of hydration of the skin and skin whitening potential, while no significant changes in TEWL and pH values were detected. The consistency, firmness and stickiness of the emulgels were estimated by volunteers applying the established sensory evaluation protocol. In addition, it was revealed that the difference in hydrophilic/lipophilic properties of L-ascorbic acid derivatives influenced their release profiles without changing their textural characteristics. Therefore, this study highlighted emulgels as L-ascorbic acid suitable carrier systems and one of the promising candidates as novel drug delivery systems. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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Review

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16 pages, 1396 KiB

Open AccessReview

Strategies for Improving Transdermal Administration: New Approaches to Controlled Drug Release

by Olimpia Dumitriu Buzia, Ana Maria Păduraru, Claudia Simona Stefan, Monica Dinu, Dorin Ioan Cocoș, Lawrence Chukwudi Nwabudike and Alin Laurențiu Tatu

Pharmaceutics 2023, 15(4), 1183; https://doi.org/10.3390/pharmaceutics15041183 - 07 Apr 2023

Cited by 8 | Viewed by 2096

Abstract

In this work, we aim to address several strategies to improve transdermal drug delivery, such as iontophoresis, sonophoresis, electroporation and micron. We also propose a review of some transdermal patches and their applications in medicine. TDDs (transdermal patches with delayed active substances) are multilayered pharmaceutical preparations that may contain one or more active substances, of which, systemic absorption is achieved through intact skin. The paper also presents new approaches to the controlled release of drugs: niosomes, microemulsions, transfersomes, ethosomes, but also hybrid approaches nanoemulsions and microns. The novelty of this review lies in the presentation of strategies to improve the transdermal administration of drugs, combined with their applications in medicine, in light of pharmaceutical technological developments. Full article

(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery, 2nd Edition)

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